DE2845857C2 - Benzo [d] thiazole derivatives, processes for their preparation and pharmaceutical preparations containing them - Google Patents
Benzo [d] thiazole derivatives, processes for their preparation and pharmaceutical preparations containing themInfo
- Publication number
- DE2845857C2 DE2845857C2 DE2845857A DE2845857A DE2845857C2 DE 2845857 C2 DE2845857 C2 DE 2845857C2 DE 2845857 A DE2845857 A DE 2845857A DE 2845857 A DE2845857 A DE 2845857A DE 2845857 C2 DE2845857 C2 DE 2845857C2
- Authority
- DE
- Germany
- Prior art keywords
- formula
- compounds
- preparation
- benzo
- processes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000002360 preparation method Methods 0.000 title description 4
- 238000000034 method Methods 0.000 title description 3
- 239000000825 pharmaceutical preparation Substances 0.000 title description 3
- 230000008569 process Effects 0.000 title description 3
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 5
- RMFVVPBBEDMZQI-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1,3-benzothiazole Chemical class C1CCCC2=C1N=CS2 RMFVVPBBEDMZQI-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 238000009835 boiling Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 4
- 208000001953 Hypotension Diseases 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- -1 ethanol Chemical compound 0.000 description 4
- 230000000763 evoking effect Effects 0.000 description 4
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 3
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 3
- 229940025084 amphetamine Drugs 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 210000001105 femoral artery Anatomy 0.000 description 3
- 230000036543 hypotension Effects 0.000 description 3
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 3
- 229960003147 reserpine Drugs 0.000 description 3
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 210000002820 sympathetic nervous system Anatomy 0.000 description 3
- QVVAWONRFLJUBP-UHFFFAOYSA-N 1,3-benzothiazol-3-ium;chloride Chemical compound Cl.C1=CC=C2SC=NC2=C1 QVVAWONRFLJUBP-UHFFFAOYSA-N 0.000 description 2
- OQDPVLVUJFGPGQ-UHFFFAOYSA-N 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]pyrimidine Chemical compound C=1C=C2OCOC2=CC=1CN(CC1)CCN1C1=NC=CC=N1 OQDPVLVUJFGPGQ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 206010015995 Eyelid ptosis Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 229960000959 amineptine Drugs 0.000 description 2
- VDPUXONTAVMIKZ-UHFFFAOYSA-N amineptine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2C([NH2+]CCCCCCC(=O)O)C2=CC=CC=C21 VDPUXONTAVMIKZ-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000002891 anorexigenic effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000003943 catecholamines Chemical class 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229960003878 haloperidol Drugs 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 230000004899 motility Effects 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229960004310 piribedil Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 201000003004 ptosis Diseases 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000000021 stimulant Substances 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 240000007711 Peperomia pellucida Species 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000578 anorexic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- YJHNHFAMPPBTPK-UHFFFAOYSA-N ethyl 2-methyl-6-oxo-5,7-dihydro-4h-1,3-benzothiazole-7-carboxylate Chemical compound C1CC(=O)C(C(=O)OCC)C2=C1N=C(C)S2 YJHNHFAMPPBTPK-UHFFFAOYSA-N 0.000 description 1
- RVJDQDKTSBEQEK-UHFFFAOYSA-N ethyl 6-oxo-5,7-dihydro-4h-1,3-benzothiazole-7-carboxylate Chemical compound C1CC(=O)C(C(=O)OCC)C2=C1N=CS2 RVJDQDKTSBEQEK-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Description
(H)(H)
in denen R für Wasserstoff oder einen Q — G»-AIkylrest und R' für Wasserstoff oder einen -Methylrest stehen, wobei R und R' nicht gleichzeitig Wasserstoff bedeuten, und X- ein durch eine pharmazeutisch unbedenkliche Säure gebildetes Anion istin which R stands for hydrogen or a Q - G »- alkyl radical and R 'for hydrogen or a - methyl radical stand, where R and R 'are not simultaneously hydrogen, and X- is an anion formed by a pharmaceutically acceptable acid
Z 6-MethyIamino-4^,6,7-tetrahydrobenzo[d]thiazol und seine Additonssalze mit pharmazeutisch unbedenklichen Säuren.Z 6-MethyIamino-4 ^, 6,7-tetrahydrobenzo [d] thiazole and its addition salts with pharmaceutical harmless acids.
3. Verfahren zur Herstellung von Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man3. Process for the preparation of compounds according to claim 1, characterized in that one
a) mit einem halogenierten Ketoester der allgemeinen Formela) with a halogenated ketoester of the general formula
Y C2H5OCO-CH2-CH-CO(CHj)2-COOCiH5 YC 2 H 5 OCO-CH 2 -CH-CO (CHj) 2 -COOCiH 5 (ΠΙ)(ΠΙ)
in der Y ein Halogenatom ist, ein Thioamid der allgemeinen Formelin which Y is a halogen atom, a thioamide of general formula
R-C-NH2 RC-NH 2
in der R die in Anspruch 1 genannte Bedeutung hat, in einem Lösungsmittel umsetzt, b) das erhaltene Thiazol der allgemeinen Formelin which R has the meaning given in claim 1 has reacted in a solvent, b) the obtained thiazole of the general formula
3535
(V)(V)
in Gegenwart eines Alkalialkoholates in einem Äther oder einem gesättigten oder aromatischen Kohlenwasserstoff unter den üblichen Bedingungen der Dieckmann-Cyclisierung cyclisiert,in the presence of an alkali alcoholate in an ether or a saturated or aromatic hydrocarbon among the usual Conditions of the Dieckmann cyclization cyclized,
die erhaltene Verbindung heiß in einem sauren oder wäßrigen Medium oder einem wäßrigen Alkohol hydrolysiertthe compound obtained hot in an acidic or aqueous medium or an aqueous one Hydrolyzed alcohol
das hierbei erhaltene Keton der allgemeinen so Formelthe resulting ketone of the general formula
O = CO = C
(VII)(VII)
mit einem Amin der allgemeinen Formel R'-NH2, worin R' die in Anspruch 1 genannte Bedeutung hat, umsetzt und das hierbei erhaltene Imin der allgemeinen Formelwith an amine of the general formula R'-NH 2 , in which R 'has the meaning given in claim 1, and the resulting imine of the general formula
CH2 CH 2
(VIII)(VIII)
(CHj)2 (CHj) 2
hydriert und gewünschtenfalls die erhaltene Base in ein pharmazeutisch unbedenkliches Säureadditionssalz überführt.hydrogenated and, if desired, the base obtained into a pharmaceutically acceptable one Acid addition salt transferred.
4. Arzneimittelzubereitung, enthaltend eine Verbindung nach Anspruch I oder 2 zusammen mit üblichen Träger- und Hilfsstoffen.4. A pharmaceutical preparation containing a compound according to claim I or 2 together with common carriers and auxiliary materials.
Die Erfindung betrifft 4,5,6,7-TetrahydroHenzothiazo-Ie, ein Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittelzubereitungen, wie in den Ansprüchen dargelegt.The invention relates to 4,5,6,7-TetrahydroHenzothiazo-Ie, a process for their preparation and them containing pharmaceutical preparations as set out in the claims.
Als Additionssalze kommen insbesondere solche mit Salzsäure, Bromwasserstoffsäure, Schwefelsäure und pharmazeutisch unbedenklichen organischen Säuren in Frage.As addition salts come in particular those with hydrochloric acid, hydrobromic acid, sulfuric acid and pharmaceutically acceptable organic acids in question.
Die Verbindungen der Formel (I) können wie folgt hergestellt werden:The compounds of formula (I) can be prepared as follows:
In der Stufe a) des Herstellungsverfahrens kann das Lösungsmittel, insbesondere ein Alkohol wie Äthanol sein und die Umsetzung gegebenenfalls in Gegenwart von Pyridin erfolgen.In stage a) of the manufacturing process, the Solvent, in particular an alcohol such as ethanol, and the reaction, if appropriate, in the presence done by pyridine.
In der Stufe b) kann das Alkalialkoholat z. B. Natriumathylat und der aromatische Kohlenwasserstoff z. B. Benzol sein.In stage b) the alkali metal alcoholate can, for. B. sodium ethylate and the aromatic hydrocarbon z. B. be benzene.
Die beiden Arbeitsschritte in der Stufe (d) können gleichzeitig oder nacheinander durchgeführt werden.The two working steps in stage (d) can be carried out simultaneously or in succession.
μ Beispielsweise kann das Amin R'NHj in einer Wasserstoffatmosphäre unter Druck bei gewöhnlicher Temperatur oder in der Wärme in Gegenwart eines Katalysators, z. B. Raney-Nickel, und in einem Lösungsmittel, z. B. einem Alkohol, umgesetzt werden. Es istμ For example, the amine R'NHj in a hydrogen atmosphere under pressure at ordinary temperature or in the heat in the presence of a Catalyst, e.g. B. Raney nickel, and in a solvent, e.g. B. an alcohol are implemented. It is
61S auch möglich, allein das Amin der Formel R'NH2 in alkoholischer Lösung umzusetzen, das gebildete Imin der Formel (VIII) zu isolieren und es in Gegenwart eines Katalysators, z. B. Raney-Nickel, Platinkohle oder6 1 S also possible to implement the amine of the formula R'NH2 alone in alcoholic solution, to isolate the imine of the formula (VIII) formed and to remove it in the presence of a catalyst, e.g. B. Raney nickel, platinum or
Die Verbindungen der Formel (II) werden in üblicher Weise durch Einwirkung einer Säure auf eine Verbindung der Formel (1) in einem geeigneten Lösungsmittel hergestellt The compounds of the formula (II) are prepared in a customary manner by the action of an acid on a compound of the formula (1) in a suitable solvent
Die Herstellung der Verbindungen der Formeln (!) und (II) wird durch die folgenden Beispiele veranschaulicht The preparation of the compounds of the formulas (!) And (II) is illustrated by the following examples
Beispiel 1
a)3-Brom-4-oxo-äthylpimelat(Formel III)example 1
a) 3-Bromo-4-oxo-ethyl pimelate (Formula III)
115 g (0,5 Mol) 4-Oxo-äthylpimelat werden in 150 ml Äthyläther gelöst Der Lösung werden 80 g (0,5 Mol) Brom unter Rühren zugesetzt Nach vollständiger Umsetzung des Broms wird die Lösung unter vermindertem Druck eingeengt und der Rückstand neutral gewaschen, unter vermindertem Druck getrocknet und in roher Form für die folgenden Reaktionen verwendet115 g (0.5 mol) of 4-oxo-ethyl pimelate are dissolved in 150 ml Dissolved ethyl ether. 80 g (0.5 mol) of bromine are added with stirring to the solution Implementation of the bromine, the solution is concentrated under reduced pressure and the residue is neutral washed, dried under reduced pressure, and used in crude form for the following reactions
b)2-MethyI-5-äthoxycarbonylmethyl-b) 2-MethyI-5-ethoxycarbonylmethyl-
4-(2-ätho*ycarbonyIäthyI)-thiazol4- (2-ethoxy-carbonyl-ethyI) -thiazole
(Forme! V; R = CHj)(Form! V; R = CHj)
Das in der Stufe (a) erhaltene rohe Produkt wird in 150 ml wasserfreiem Äthanol mit 37,5 g (0,5 Mol) Thioacetamid gelöst Das Gemisch wird 70 Stunden bei Umgebungstemperatur gerührt, worauf das Äthanol abdestilliert und der Rückstand hi Wasser und Äthyläther aufgenommen wird. Die Ätherphase wird mehrmals mit 2n-Schwefelsäure extrahiert und dann mit der wäßrigen Phase vereinigt Diese wird auf pH 7 eingestellt Das sich abscheidende öl wird mit Äther extrahiert und unter vermindertem Druck destilliertThe crude product obtained in step (a) is dissolved in 150 ml of anhydrous ethanol with 37.5 g (0.5 mol) Thioacetamide dissolved. The mixture is stirred at ambient temperature for 70 hours, whereupon the ethanol distilled off and the residue is taken up hi water and ethyl ether. The ether phase becomes extracted several times with 2N sulfuric acid and then combined with the aqueous phase. This is brought to pH 7 The oil which separates out is extracted with ether and distilled under reduced pressure
Siedepunkt 135-140°C/0Z" mbar; Gewicht 78,5 g; Gesamtausbeute 54%.Boiling point 135-140 ° C / 0Z "mbar; weight 78.5 g; Overall yield 54%.
c) 2-Methyl-7-äthoxycarbonyl-6 oxo-4,5,6.7-tetrahydrobenzo[d]thiazol c) 2-methyl-7-ethoxycarbonyl-6 oxo-4,5,6,7-tetrahydrobenzo [d] thiazole
Eine frische Suspension von Natriumäthylat in Äthyläther wird durch Auflösen von 5,7 g (0,248 g-Atom) Natrium und 200 ml wasserfreiem Äthanol hergestellt Das Äthanol wird abgedampft und der Rückstand in 200 ml wasserfreiem Äther aufgenommen. Zum Gemisch werden 70,5 g (0,248 Mol) des in der Stufe (b) erhaltenen Produkts gegeben. Das Gemisch wird 40 Stunden bei Umgebungstemperatur gerührt, mit 15 g (0,250 Mol) Essigsäure versetzt und zur Trockene eingedampft Der Rückstand wird in Wasser und Äthylacetat aufgenommen. Die organische Phase wird abgetrennt und destilliert. Der Rückstand wird unter vermindertem Druck destilliert.A fresh suspension of sodium ethylate in ethyl ether is made by dissolving 5.7 g (0.248 g-atom) Sodium and 200 ml of anhydrous ethanol produced. The ethanol is evaporated and the The residue was taken up in 200 ml of anhydrous ether. To the mixture are 70.5 g (0.248 mol) of the in the stage (b) given product obtained. The mixture is stirred for 40 hours at ambient temperature, with 15 g (0.250 mol) of acetic acid are added and the mixture is evaporated to dryness. The residue is dissolved in water and Ethyl acetate added. The organic phase is separated off and distilled. The residue is taking distilled under reduced pressure.
Siedepunkt 135-140°C/0,4 mbar (mit leichter Zersetzung); Ausbeute 95%.Boiling point 135-140 ° C / 0.4 mbar (with slight decomposition); Yield 95%.
Die Stellung der Äthoxycarbonylgruppe könnte sich gemäß der Dickmannschen Cyclisierungsrichtung ä priori am 7-Kohlenstoff (Formel A) oder am 5-Kohlenstoff (Formel B) befinden. Der Zweifel wurde durch das NMR-Spektrum behoben, das das Fehlen der Kupplung mit dem isolierten Proton, das sich an dem die Gruppe COOC2Hs tragenden Kohlenstoffatom befindet, anzeigt. Dies ist nur mit der Formel A vereinbar.According to Dickmann's cyclization direction, the position of the ethoxycarbonyl group could be a priori on the 7-carbon (formula A) or on the 5-carbon (formula B). The doubt was resolved by the NMR spectrum, which shows the lack of coupling with the isolated proton located on the carbon atom bearing the group COOC 2 Hs. This is only compatible with Formula A.
CH3 CH 3
(A)(A)
C2H5OCO HC 2 H 5 OCO H
d) 2-Methyl-6-oxo-4A6,7-tetraliydrobenzo[d]thiazol
(Formel VII;R=CH3)d) 2-Methyl-6-oxo-4A6,7-tetralihydrobenzo [d] thiazole
(Formula VII; R = CH 3 )
Ein Gemisch von 10 g (0,042 Mol des in der Stufe (c)
erhaltenen Ketoesters und 100 ml 1 η-Salzsäure wird 24
Stunden am Rückfluß erhitzt Nach Entfärbung mit Kohle wird die Lösung auf pH 5 eingestellt und
mehrmals mit Äthylacetat extrahiert Durch Abdampfen des Lösungsmittels werden 6 y(86%) eines Öls erhalten,
das kristallisiert
Schmelzpunkt 95 - 96° C.A mixture of 10 g (0.042 mol of the keto ester obtained in step (c) and 100 ml of 1 η-hydrochloric acid is refluxed for 24 hours. After decolorization with charcoal, the solution is adjusted to pH 5 and extracted several times with ethyl acetate. By evaporating the solvent 6 y (86%) of an oil are obtained which crystallizes
Melting point 95 - 96 ° C.
e)2-MethyI-6-amino-4,5,6,7-tetrahydro-e) 2-MethyI-6-amino-4,5,6,7-tetrahydro-
benzo[d]thiazolhydrochlorid
(Formel II; R = CH3; R' = H, X = Cl)benzo [d] thiazole hydrochloride
(Formula II; R = CH 3 ; R '= H, X = Cl)
In 200 ml Äthanol werden 9 g (0,054 Mol) des in der Stufe (d) erhaltenen Produkts gelöst Die Lösung wird mit 20 g Ammoniak und 5 g Raney-Nickel in einen Autoklaven gegeben. Der Autoklav wird mit Wasserstoff unter einem Gesamtdruck von 55 bar gefüllt und 2 Stunden bei 1000C erhitzt Nach der Abkühlung, Filtration des'Katalysators und nach dem Eindampfen des Alkohols wird das als Rückstand verbleibende Öl fraktioniert9 g (0.054 mol) of the product obtained in step (d) are dissolved in 200 ml of ethanol. The solution is placed in an autoclave with 20 g of ammonia and 5 g of Raney nickel. The autoclave is filled with hydrogen at a total pressure of 55 bar and for 2 hours at 100 0 C heated after cooling, filtration des'Katalysators and after evaporation of the alcohol, the oil remaining as residue is fractionated
Siedepunkt 110- 130° 00,67 mbar.Boiling point 110-130 ° 00.67 mbar.
Die Base wird in Form des Carbonats gereinigt,The base is purified in the form of the carbonate,
indem CO2 in eine Lösung in Äther eingeleitet wird. Dasby bubbling CO 2 into a solution in ether. That
ausgefällte Carbonat wird abgenutscht mit Äther gewaschen und unter Vakuum getrocknet Die Base (V) wird durch Erhitzen auf 100° C unter 20 mbar isoliertprecipitated carbonate is filtered off with suction, washed with ether and dried under vacuum The base (V) is isolated by heating to 100 ° C under 20 mbar
Siedepunkt 120- 130°C/0,665 mbar.Boiling point 120-130 ° C / 0.665 mbar.
Auf Grund ihrer Oxydierbarkeit wird die Base durch Zusatz von wasserfreier Salzsäure im leichten Unterschuß in Ätherlösung unmittelbar in das Hydrochlorid umgewandeltBecause of its ability to be oxidized, the base becomes slightly deficient when anhydrous hydrochloric acid is added converted directly into the hydrochloride in ethereal solution
Schmelzpunkt 255° C (Zers.). Gesamtausbeute 67%.Melting point 255 ° C (decomp.). Overall yield 67%.
2-Methyl-6-methylamino-4,5,6,7-tetra-2-methyl-6-methylamino-4,5,6,7-tetra-
hydrobenzo[d]thiazol
(Formel I; R = R' = CHj)hydrobenzo [d] thiazole
(Formula I; R = R '= CHj)
Zu einer Lösung von 10 g (0,062 Mol) des in der Stufe so (d) von Beispiel 1 erhaltenen Produkts in 200 ml Äthanol wenden 20 g Methylamin und 5 g Raney-Nickel gegeben, worauf im Autoklaven unter einem Druck von 55 bar unter den in Beispiel 1 (e) genannten Bedingungen hydriert wird. Die Base wird durch Abdampfen des Lösungsmittels in einer Ausbeute von 72% erhalten. Siedepunkt 86-88°C/0,133 mbar.To a solution of 10 g (0.062 mol) of the in the stage Product obtained in this way (d) from Example 1 in 200 ml of ethanol apply 20 g of methylamine and 5 g of Raney nickel given, whereupon in the autoclave under a pressure of 55 bar under the conditions mentioned in Example 1 (e) is hydrogenated. The base is obtained in 72% yield by evaporating the solvent. Boiling point 86-88 ° C / 0.133 mbar.
Die Base wird mit wasserfreiem HCI in Ätherlösung quantitativ in das Hydrochlorid umgewandelt (Formel
(lI),m=1,n=2,R = R' = CHJ.X = CI).
Schmelzpunkt 260°C (Zers.).The base is converted quantitatively into the hydrochloride with anhydrous HCl in ethereal solution (formula (III), m = 1, n = 2, R = R '= CH J .X = CI).
Melting point 260 ° C (decomp.).
a)5-Äthoxycarbonylmethyl-4-(2-äthoxy-a) 5-ethoxycarbonylmethyl-4- (2-ethoxy-
carbonyläthyl)-thiazolcarbonylethyl) thiazole
(Formel V; R = H)(Formula V; R = H)
212,5 g (0,68 Mol) 3-Brom-4-oxoäthylpimelat (in der Stufe (a) von Beispiel 1 erhalten) werden in 380 ml212.5 g (0.68 mol) of 3-bromo-4-oxoethyl pimelate (obtained in step (a) of Example 1) are dissolved in 380 ml
wasserfreiem Äthanol gelöst Zur Lösung werden 41,6 g (0,68 MoI) frisch hergestelltes Ihioformamid gegeben. Nach der exothermen Anfangsreaktion wird das Gemisch 20 Stunden bei Umgebungstemperatur gehalten. Das Äthanol wird unter vermindertem Druck abgedampft und der Rückstand in Äther aufgenommen. Das in Äther unlösliche Hydrobromid des gebilc!??cn Produkts wird abgenutscht, in der Mindesunenge Wasser gelöst und mit gesättigter wäßriger Natriumbicarbonatlösung auf pH ύ eingestellt. Die Base wird mit Äthylacetet extrahiert, mit Wasser gewaschen, getrocknet und unter vermindertem Druck destilliertDissolved anhydrous ethanol. 41.6 g (0.68 mol) of freshly prepared ihioformamide are added to the solution. After the initial exothermic reaction, the mixture is kept at ambient temperature for 20 hours. The ethanol is under reduced pressure evaporated and the residue taken up in ether. The ether-insoluble hydrobromide des gebilc! ?? cn Product is sucked off in the minimum tightness Dissolved water and adjusted to pH ύ with saturated aqueous sodium bicarbonate solution. The base is with Ethyl acetate extracted, washed with water, dried and distilled under reduced pressure
Siedepunkt 139-148°C/0,67 mbar. Gewicht 84 g (45%).Boiling point 139-148 ° C / 0.67 mbar. Weight 84 g (45%).
b) 7-Äthoxycarbonyl-6-oxo-4,5,6,7-tetrahydrobenzo[d]thiazolb) 7-ethoxycarbonyl-6-oxo-4,5,6,7-tetrahydrobenzo [d] thiazole
Diese Verbindung wird aus dem in der Stufe (a) erhaltenen Produkt auf die in Beispiel 1 (c) beschriebene Weise hergestellt Das Produkt das kristallisiert wird aus Isopropyloxyd umkristallisiertThis compound is converted from the product obtained in step (a) to that described in Example 1 (c) Wise prepared The product that crystallizes is recrystallized from isopropyl oxide
2525th
c)6-Oxo-4A6,7-tetrahydrobenzo[djthia7.oI (Formel VII; R = H)c) 6-Oxo-4A6,7-tetrahydrobenzo [djthia7.oI (Formula VII; R = H)
Diese Verbindung wird durch Hydrolyse und Decarboxylierung des in der Stufe (b) erhaltenen Ketoesters auf die in Beispiel 1 (d) beschriebene Weise hergestellt Ausbeute 85% (an der Luft wenig stabiles Produkt).This compound is obtained by hydrolysis and decarboxylation of that obtained in the step (b) Ketoesters prepared in the manner described in Example 1 (d). Yield 85% (not very stable in air Product).
d)6-MethyIamino-4,5,6,7-tetrahydro-d) 6-MethyIamino-4,5,6,7-tetrahydro-
benzo[d]thiazolhydrochlorid (Formel II; R = H, R' = CH3, X = Cl)benzo [d] thiazole hydrochloride (formula II; R = H, R '= CH 3 , X = Cl)
Die Verbindung wird durch Einwirkung von Methylamin auf das in der Stufe (c) erhaltene Keton in Gegenwart von Wasserstoff und Raney-Nickel auf die in Beispiel 1 (e) beschriebene Weise hergestellt Die Base de. Formel (I) wird unter vermindertem Druck destilliertThe compound is by the action of methylamine on the ketone obtained in step (c) in The presence of hydrogen and Raney nickel prepared in the manner described in Example 1 (e) Base de. Formula (I) is distilled under reduced pressure
Das Hydrochlorid wird durch Zusatz von in Äthyläther gelöster wasserfreier Salzsäure im leichten Unterschuß gebildetThe hydrochloride is made easy by adding anhydrous hydrochloric acid dissolved in ethyl ether Deficit formed
In den folgenden Tabellen sind die Kennzahlen der gemäß den vorstehenden Beispielen hergestellten Verbindungen der Formel (I) (Tabelle I) sowie die Kennzahlen anderer Verbindungen der Formeln (I) und (II), die in analoger Weise hergestellt worden sind (Tabelle Umgenannt The tables below show the key figures for the compounds of the formula (I) prepared according to the above examples (Table I) and the key figures for other compounds of the formulas (I) and (II) which have been prepared in an analogous manner (table renamed
Tabelle ΠTable Π
Beispielexample
Ausbeute,Yield,
Siedepunkt, °C/mbarBoiling point, ° C / mbar
1515th
3535 Die Verbindungen der Formel (I) und ihre Salze der Formel (H) weisen interessante pharmakologische Eigenschaften auf, die in allgemeiner Weise auf einer Wechselwirkung mit den Aminen des sympathischen Nervensystems, insbesondere mit Dopamin, beruhen. Sie weisen somit je nach den L' ständen hypertensive oder hypotensive, anorexägene, i.n?!getische und entzündungshemmende, stimulierende oder sedierende Wirkungen auf das sympathische Nervensystem im zentralen oder peripheren Teil auf.The compounds of formula (I) and their salts of Formula (H) have interesting pharmacological properties that are generally based on a Interaction with the amines of the sympathetic nervous system, especially with dopamine, based. Depending on the level, they indicate hypertensive or hypotensive, anorexagenic, i.n? !Getic and anti-inflammatory, stimulating or sedating Effects on the sympathetic nervous system in the central or peripheral part.
Diese Eigenschaften wurden mit Hilfe der folgenden klassischen Tests nachgewiesen:These properties have been demonstrated using the following classic tests:
1) Für das Zentralnervensystem:1) For the central nervous system:
hervorgerufenen Schlafs,evoked sleep,
hervorgerufenen Stereotypien,evoked stereotypes,
hervorgerufenen Ptosis.evoked ptosis.
2) Für die Analgesie:2) For analgesia:
0.75%iger Essigsäure bei der Maus auftreten0.75% acetic acid can occur in the mouse (Koster-Test),(Koster test),
3) Für die Entzündung:3) For inflammation:
Hemmung des durch subkutane Injektion von Carrageenin bei der Ratte hervorgerufenen Ödems am Fuß.Inhibition of edema induced by subcutaneous injection of carrageenin in the rat at the foot.
4) Für das kardiovaskuläre System:4) For the cardiovascular system:
Messung des Blutdrucks, des Durchflusses durch die Femoralarterie und der Herzfrequenz und Suche nach einem Antagonismus oder einer Verstärkung der Wirkung dtr Katecholamine (Adrenalin, Noradrenalin) auf diese Parameter beim Hund; Measuring blood pressure, femoral artery flow and heart rate and looking for an antagonism or enhancement of the effect of dtr catecholamines (adrenaline, noradrenaline) on these parameters in the dog;
Untersuchungen über eine Wirkung auf die glatten Fasern der isolierten Vena sphena des Hundes und auf die isolierte Arterie des Kaninchenohrs in vitro.Investigations into an effect on the smooth Fibers of the isolated canine sphena vein and of the isolated artery of the rabbit ear in vitro.
Die untersuchten Verbindungen wurden in Form der Hydrochloride entweder intraperitoneal (oder bei den kardiovaskulären Versuchen intravenös) oder oral verabreicht.The compounds examined were either administered intraperitoneally (or with the cardiovascular trials intravenously) or orally.
Die untersuchten Verbindungen zeigen im allgemeinen in unterschiedlichem MaOeThe compounds examined generally show in different degrees
a) eine zentral stimulierende Wirkung (Steigerung der Spontanmotalität, der auf Amphetamin hervorgerufenen Stereotypien, Antagonismus von Reserpin) begleitet zuweilen von einer anorexigenen Wirkung (Verringerung der Futteniufnahme bei der Ratte),a) a centrally stimulating effect (increase in Spontaneous totality, amphetamine-evoked stereotypes, reserpine antagonism) sometimes accompanied by an anorexic effect (reduction in food consumption in the Rat),
b) eine zuweilen starke analgetische Wirkung sowie eine entzündungshemmende Wirkung undb) a sometimes strong analgesic effect and an anti-inflammatory effect and
c) eine zweiphasige kardiovaskuläre Wirkung, diec) a two-phase cardiovascular effect that
inin
gekennzeichnet ist durch Hypotension und Vasotli· latation bei geringen Dosen und durch eine Hypertension, die ihren Ursprung in einer sowohl in vitro als auch in vivo zu beobachtenden Vasokonstriktion hat,bei hohen Dosen.is characterized by hypotension and vasotlatation at low doses and by a Hypertension originating in an observable both in vitro and in vivo Has vasoconstriction at high doses.
Diese Wirkungen kommen insgesamt denen nahe, die bei Katechnlaminen und insbesondere bei dopaminergisehen Stimulantien beobachtet werden.Overall, these effects are close to those seen with catecholamines and especially with dopaminergic drugs Stimulants are observed.
Nachstehend werden als Beispiele die b;ii gewissen Verbindungen erhaltenen Ergebnisse genannt.The following are examples of the results obtained from certain compounds.
Hemmung der durch
Reserpin ausgelösten
Ptosis bei 10 mg/kg
(40%)Inhibition of by
Reserpine-triggered
Ptosis at 10 mg / kg
(40%)
Steigerung der durch
Amphetamin ausgelösten Stereotypien
und anorexigene Wirkung bei 3 mg/kgIncrease through
Amphetamine-induced stereotypes
and anorexigenic effects at 3 mg / kg
Steigerung der Spontanmotilität und der
Amphetamin ausgelösten Stereotypien
bei 3 mg/kg
Anorexigene Wirkung
bei 3 mg/kgIncrease in spontaneous motility and the
Amphetamine-induced stereotypes
at 3 mg / kg
Anorexigenic effects
at 3 mg / kg
3030th
<3<3
30 Hypotension bei 0,5 mg/kg30 hypotension at 0.5 mg / kg
Hypertension bei 1-5 mg/kg
Kontraktion der isolierten Venen und Arterien bei 2x10" g/mlHypertension at 1-5 mg / kg
Contraction of the isolated veins and arteries at 2x10 "g / ml
< 10 Hypotension bei 0,5 mg/kg<10 hypotension at 0.5 mg / kg
Hypertension bei 1 mg/kg unter
Steigerung des Durchflusses
durch die Femoralarterie;
Kontraktion der isolierten Venen und Arterien bei 2 X 10"s g/mlHypertension at 1 mg / kg below
Increase in flow
through the femoral artery;
Contraction of the isolated veins and arteries at 2 X 10 " s g / ml
<30 Hypertension bei 1 bis 5 mg/kg<30 hypertension at 1 to 5 mg / kg
mit starker Steigerung des Durchflusses durch die Femoralarterie; Kontraktion der isolierten Vene
bei 10"5 g/ml
0 bei der isolierten Arteriewith a sharp increase in the flow through the femoral artery; Contraction of the isolated vein
at 10 " 5 g / ml
0 for the isolated artery
Außerdem übt die gemäß Beispiel 3 hergestellte Verbindung einen deutlichen zerebralen Schutzeffekt gegenüber hypoxischer Asphyxie unter vermindertem Sauerstoffdruck aus. Andererseits hemmt die gleiche Verbindung stark das Auftreten von durch Streß hervorgerufenen Magengeschwüren bei der Ratte.In addition, the compound prepared according to Example 3 has a clear cerebral protective effect against hypoxic asphyxia under reduced oxygen pressure. On the other hand, the same inhibits Strongly related to the occurrence of stress-induced gastric ulcer in the rat.
Die akute Toxizität bei der Maus ist sowohl bei intraperitonealer als auch oraler Verabreichung gering.The acute toxicity in the mouse is low with both intraperitoneal and oral administration.
5555
Verbindung von
Beispiel Nr.connection of
Example no.
Akute Toxizität, DL50, mg/kg i. p. p. 0. Acute toxicity, DL 50 , mg / kg ipp 0.
6060
<100
>100
>200<100
> 100
> 200
>200 >200 >200> 200> 200> 200
Die Verbindungen der Formel (I) und ihre Salze der Formel (II) können als Stimulantien des sympathischen Nervensystems, als Regulatoren des allgemeinen Gefäßsystems und insbesondere des zerebralen Gefäßsystems, als Anaigetika und entzündungshemmende Mittel sowie als Mittel gegen Geschwürsbildung verwendet werden. Die in Beispiel 3 beschriebene Verbindung erweist sich in dieser Hinsicht als besonders interessant, ohne nennenswerte Toxizität bei den wirksamen Dosen zu zeigen.The compounds of formula (I) and their salts of formula (II) can be used as stimulants of the sympathetic Nervous system, as regulators of the general vascular system and in particular of the cerebral vascular system, as anesthetics and anti-inflammatory agents, and as anti-ulcer agents be used. The compound described in Example 3 proves to be special in this regard interesting without showing any significant toxicity at the effective doses.
Die Verbindungen werden dem Menschen oral oder rektal in Form der Basen oder Salze (als Tabletten, Kapseln, Tropfen oder Suppositorien) oder parenteral in Form von wäßrigen Lösungen der wasserlöslichen Salze verabreicht Diese verschiedenen Arzneiformen können 50 bis 500 mg Wirkstoff pro Dosierungseinheit enthalten. Die Tagesdosis beim Erwachsenen kann von 50 mg bis 2 g in Abhängigkeit von den vorliegenden therapeutischen Indikationen variieren.The compounds are administered orally or rectally to humans in the form of bases or salts (as tablets, Capsules, drops or suppositories) or parenterally in the form of aqueous solutions of the water-soluble Salts administered These different dosage forms can contain 50 to 500 mg of active ingredient per dosage unit contain. The daily dose in adults can range from 50 mg to 2 g depending on the present therapeutic indications vary.
Die Verbindungen gemäß vorliegender Erfindung besitzen besonders stimulierende Wirkungen auf das Zentralnervensystem auf dem Niveau der zentralen Dopaminrezeptoren.The compounds according to the present invention have particularly stimulating effects on the Central nervous system at the level of the central dopamine receptors.
Die Verbindungen gemäß der Erfindung wurden mit dem Piribedil und dem Amineptine verglichen, die bekannt sind und als Stimulantien des Zentralnervensystems verwendet werden.The compounds according to the invention were compared with the Piribedil and the Amineptine, which are known and used as central nervous system stimulants.
Die Versucbsmethode bestand darin, daß die zu untersuchenden Verbindungen Ratten subkutan verabreicht wurden und daß die minimale aktive Dosis bestimmt wurde, die die Erscheinung von Stereotypien hervorruft.The experimental method was that the compounds to be tested were administered subcutaneously to rats and that the minimum active dose was determined that the appearance of stereotypes evokes.
Für alle geprüften Verbindungen wurde gleichfalls die zentrale stimulierende dopaminergische Wirkung charakterisiert, indem man einen spezifischen Antagonisten für diese Rezeptoren verwendete, und zwar das Haloperidol. das vor der subkutanen Injektion der zu priifenden Verbindungen intraperitoneal in einer Dosis von 2 mg/kg verabreicht wurde. In allen Fällen unterdrückte das Haloperidol die Stereotypien. Dies bestiitigt die Identität des Wirkungsmechanismus der Verbindungen gemäß der Erfindung mit den Vergleichsverbindungen. The central stimulatory dopaminergic effect characterized by targeting a specific antagonist used for these receptors, namely the haloperidol. that before the subcutaneous injection of the too test compounds was administered intraperitoneally at a dose of 2 mg / kg. In all cases the haloperidol suppressed stereotypes. This confirms the identity of the mechanism of action of the Compounds according to the invention with the comparison compounds.
Die DL,n wurde intraperitoneal an der Maus bestimmt.The DL, n was determined intraperitoneally on the mouse.
Verbindunglink
Minimale aktive Dosis mg/kg subkutanMinimum active dose mg / kg subcutaneously
DL5n i. p.DL 5n ip
DL50 DL 50
minimale aktive Dosisminimum active dose
Beispiel 1
Beispiel 2
Beispiel 3
Beispiel 5
Beispiel 6
Piribedil
Amineptineexample 1
Example 2
Example 3
Example 5
Example 6
Piribedil
Amineptine
3
3
33
3
3
>100> 100
8080
200200
370370
7575
5757
140140
420420
2727
6767
123123
7,57.5
5,75.7
4,74.7
<4,2<4.2
Aus den Ergebnissen ist klar ersichtlich, daß die Verbindungen gemäß der Erfindung einen günstigeren therapeutischen Index haben als die Vergleichsverbindungen. It is clear from the results that the compounds according to the invention are more favorable therapeutic index than the comparative compounds.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7731891A FR2406635A1 (en) | 1977-10-24 | 1977-10-24 | NEW BENZO (D) THIAZOLE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATIONS |
Publications (2)
Publication Number | Publication Date |
---|---|
DE2845857A1 DE2845857A1 (en) | 1979-04-26 |
DE2845857C2 true DE2845857C2 (en) | 1982-10-28 |
Family
ID=9196842
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE2845857A Expired DE2845857C2 (en) | 1977-10-24 | 1978-10-21 | Benzo [d] thiazole derivatives, processes for their preparation and pharmaceutical preparations containing them |
Country Status (10)
Country | Link |
---|---|
US (1) | US4208420A (en) |
JP (1) | JPS5948831B2 (en) |
BE (1) | BE870987A (en) |
CH (1) | CH634311A5 (en) |
DE (1) | DE2845857C2 (en) |
ES (1) | ES474367A1 (en) |
FR (1) | FR2406635A1 (en) |
GB (1) | GB2007232B (en) |
HU (1) | HU175783B (en) |
IT (1) | IT1157385B (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2459239A1 (en) * | 1979-06-20 | 1981-01-09 | Logeais Labor Jacques | NOVEL AMINO DERIVATIVES OF BENZOTHIAZOLE, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION |
ATE45735T1 (en) * | 1984-12-22 | 1989-09-15 | Thomae Gmbh Dr K | TETRAHYDRO-BENZTHIAZOLE, THEIR PRODUCTION AND USE AS INTERMEDIATE OR MEDICINAL PRODUCTS. |
DE3620813A1 (en) | 1986-06-21 | 1987-12-23 | Boehringer Ingelheim Kg | NEW TETRAHYDRO-BENZOTHIAZOLES, THEIR PRODUCTION AND USE |
FR2731619A1 (en) * | 1995-03-14 | 1996-09-20 | Logeais Labor Jacques | PHARMACEUTICAL COMPOSITIONS CONTAINING L-ETRABAMINE, USES THEREOF AND PREPARATION METHODS |
DE19908539A1 (en) * | 1999-02-26 | 2000-08-31 | Aventis Pharma Gmbh | Polycyclic 2-amino-dihydrothiazole systems, processes for their preparation and their use as medicines |
WO2008001200A2 (en) * | 2006-06-29 | 2008-01-03 | Antares Pharma Ipl Ag | Transdermal composition having enhanced color stability |
CA2897459C (en) * | 2013-01-22 | 2021-03-02 | Actelion Pharmaceuticals Ltd | Heterocyclic amide derivatives as p2x7 receptor antagonists |
ES2616114T3 (en) * | 2013-01-22 | 2017-06-09 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB497659A (en) * | 1936-07-29 | 1938-12-22 | Ig Farbenindustrie Ag | Manufacture of 2-alkyl-tetrahydrobenzselenazoles |
US2882160A (en) * | 1955-05-10 | 1959-04-14 | Sperry Rand Corp | Sensitizing dyes from 2-methyl-5, 6-dihydro-4-cyclopentathiazoles |
FR2035757A1 (en) * | 1969-02-25 | 1970-12-24 | Roussel Uclaf | Novel 4-carboxy-4,5,6,7-tetrahydro benzothia- - zole derivs |
-
1977
- 1977-10-24 FR FR7731891A patent/FR2406635A1/en active Granted
-
1978
- 1978-10-03 BE BE190888A patent/BE870987A/en not_active IP Right Cessation
- 1978-10-10 GB GB7839983A patent/GB2007232B/en not_active Expired
- 1978-10-11 US US05/950,394 patent/US4208420A/en not_active Expired - Lifetime
- 1978-10-20 IT IT51589/78A patent/IT1157385B/en active
- 1978-10-20 ES ES474367A patent/ES474367A1/en not_active Expired
- 1978-10-21 DE DE2845857A patent/DE2845857C2/en not_active Expired
- 1978-10-23 CH CH1095378A patent/CH634311A5/en not_active IP Right Cessation
- 1978-10-23 JP JP53130366A patent/JPS5948831B2/en not_active Expired
- 1978-10-23 HU HU78LO427A patent/HU175783B/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
IT1157385B (en) | 1987-02-11 |
HU175783B (en) | 1980-10-28 |
ES474367A1 (en) | 1979-04-16 |
JPS5470268A (en) | 1979-06-05 |
GB2007232B (en) | 1982-03-10 |
FR2406635B1 (en) | 1980-06-27 |
FR2406635A1 (en) | 1979-05-18 |
JPS5948831B2 (en) | 1984-11-29 |
DE2845857A1 (en) | 1979-04-26 |
US4208420A (en) | 1980-06-17 |
CH634311A5 (en) | 1983-01-31 |
IT7851589A0 (en) | 1978-10-20 |
GB2007232A (en) | 1979-05-16 |
BE870987A (en) | 1979-04-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CH625522A5 (en) | ||
EP0005828B1 (en) | New substituted phenylpiperazine derivatives, pharmaceutical compositions containing them and process for their preparation | |
DE2105743C3 (en) | 2- (Furylmethyl) - a -5,9-dialkyl -6,7benzomorphane, process for their preparation and their use | |
DE3342164A1 (en) | ANTIPSYCHOTIC BENZOXAZINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM | |
DE2065636A1 (en) | NEW TRICYCLIC CONNECTIONS | |
DE2415082A1 (en) | DISUBSTITUTED PIPERAZINES, METHOD OF PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS | |
DE2845857C2 (en) | Benzo [d] thiazole derivatives, processes for their preparation and pharmaceutical preparations containing them | |
DE2720545C3 (en) | Derivatives of 2,4-diamino-6,7-dimethoxyquinazoline, their preparation and pharmaceutical agents | |
DE3016827A1 (en) | PHENYLAETHYLAMINE DERIVATIVES, THEIR PRODUCTION AND USE AND PREPARATIONS CONTAINING DERIVATIVES | |
DE2044172C3 (en) | Pyrrole derivatives, a process for their preparation and pharmaceuticals | |
DE842203C (en) | Process for the preparation of new piperazine derivatives | |
DE2711981A1 (en) | PHENAETHYLAMINE DERIVATIVES AND BRONCHODILATIVE MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS | |
DE2426149A1 (en) | FLUOROUS SUBSTITUTED PHENTHIAZINE | |
DE3233424A1 (en) | ISOCHINOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS AND THEIR USE | |
DE2900288A1 (en) | AMINO DERIVATIVES FROM PYRAZOLE SQUARE CLAMP ON 1.5 A SQUARE CLAMP ON S-TRIAZINE, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THE SAME | |
DE2503136A1 (en) | 5-METHYLTHIOPYRIMIDINE SUITABLE AS ANTIDIABETIC AND HYPOCHOLESTERINAEMIC DRUGS | |
CH640507A5 (en) | Process for preparing novel 1-aryloxy-2-hydroxy-3-aminopropanes | |
DE2024049C3 (en) | α- (3,4-Dihydroxyphenyl) -a- (2-piperidinyl) methanol | |
DE2734270C2 (en) | ||
CH647235A5 (en) | 4- (2,2-DIALKYLINDAN-1-YLIDEN) PIPERIDINE DERIVATIVES, THEIR PRODUCTION AND USE. | |
DE2907536C2 (en) | ||
DE2101691A1 (en) | Isoquinoline derivatives | |
DE2323005A1 (en) | NEW DERIVATIVES OF CUMARON AND THEIR USE AS MEDICINES | |
DE2233088A1 (en) | BENZOMORPHAN DERIVATIVES | |
DE1670017A1 (en) | Thiazine derivatives and a process for their preparation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
OAP | Request for examination filed | ||
OD | Request for examination | ||
D2 | Grant after examination | ||
8339 | Ceased/non-payment of the annual fee |